Triazine organometallic compounds and process for preparing same



Patented Nov. 17, 1953 TRIAZINE ORGANOMETALLIC COMPOUNDS AND PROCESS FORPREPARING SAME Ernst A. H. Friedheim, New York, N. Y.

No Drawing. Application January 28, 1947, Serial No. 724,925

2 Claims. 1

This invention relates to organometallic compounds containing radicalsof arsenic or antimony and has particular relation to organometalliccompounds of this type in which the radicals of arsenic or antimony arelinked to sulfur-containing organic radicals. The invention also relatesto methods of preparing such compounds.

The main object of the present invention consists in providingorganometallic compounds containing radicals of arsenic or antimony,which show valuable therapeutical properties.

Another object of my present invention is to provide organometalliccompounds of the abovementioned type which yield injectable, stablesolutions.

Other objects and the advantages of the invention will be apparent fromthe following specification and claims which show. by way of example,some preferred embodiments of the invention.

Therapeutically useful organometallic compounds of arsenic and antimonyin which the arsenic atom or antimony atom is linked to form thegrouping s- Mc and inwhich each of the two sulfur atoms is part of anindividual -SR radical (mercaptan residue) have been known. Thesecompounds correspond to the general formula Ar.Me= (SR) 2 (I) wherein Aris an organic radical, Me stands for an atom of trivalent arsenic orantimony, and SR is the residue of an organic sulfhydril compound. Thetherapeutically useful organometallic compounds, according to thepresent invention, contain radicals of trivalent arsenic and antimony inwhich the arsenic atom or antimony atom is linked to two sulfur atomswhich are substituents of the same organic radical, said organometalliccompound corresponding to the general formula Ar.Me=S2R' (II) I havefound that compounds of the above shown general structure (11) haveoutstanding chemotherapeutic, for example, trypanocidal activity,combined with relatively low toxicity. Furthermore, such compounds aredistinguished by their stability. According to the nature of thedimercapto compound used, the final product may have special propertiesof solubility which are highly desirable from the angle of practicalmedicine. For example, the combination of cer- R.MeX+ A} Rama HS- s Inthe above scheme R is an organic radical and -MeX stands for a radicalof trivalent arsenic or antimony, which is capable of reacting with thedithiol used. For example, -MeX may stand for AS=C12, As=0,As=(S.CH2COOK)2, -SbC12, Sb0, and antimony thiomalate radicals.

The organometallic compound may also be put to the reaction in thepentavalent state, provided conditions are such as to bring about in thereaction mixture a reduction to the trivalent state. This may beobtained by using an appropriate excess of the dimercapto compound whichwill act as a reducing agent.

If an aqueous reaction medium is used in a reaction with a dimercaptocompound, it is preferable to adiust the pH of the reaction mixture to 6to 8. The reaction may also be carried out in a non-aqueous medium, forexample in alcoholic or glycol solution.

Another procedure to obtain compounds corresponding to the presentinvention consists in first forming a compound of the formula withanother suitable organic compound. For example a compound of the formulamay be first prepared in the manner described in detail hereinafter andthe compound formed may be reacted with a suitable 1,3,5-triazinehalogen derivative to form a compound corresponding to the formula s-cmHsN- NH s s-cn The resulting compounds forming the object apparentlytakes place according to the following scheme:

of this invention have the following group properties:

The nitroprusside reaction for SH groups is negative or only veryfaintly positive under classical condition, 1. e. in the presence ofsodium carbonate at a. pH of about 8, but becomes positive on additionof caustic alkali, such as NaOH, 1. e. at a pH of at least 9-10.

The procedure for the preparation of the compounds embodying the presentinvention will become more apparent from the following examples.

Example 1.-36.4 millimols or sodium p-melaminylphenylstibonate (I) aresuspended in 100 ml. of water, and to this suspension 218 millimols ofammonium thioglycolate, i. e. approximately 6 equivalents based on theamount of (I) are added in concentrated (SO-58%) aqueous solution. Thereaction mixture is stirred at room temperature for 10 minutes to form anearly action mixture is filtered and the clear filtrate is diluted with200 ml. of water. 40 millimols, i. e. 10% excess of the theory, of2,3-dimercaptopropanol (II), dissolved in 20 ml. of ethanol, are addedwith rapid stirring to the reaction mixture. A white precipitate isformed immediately, filtered on, washed with 500 ml. of water. 250 ml.of ethanol and 250 ml. of ether. The washed precipitate is dried invacuo over sulfuric acid. The yield amounts to 92% of the theory.

The product thus obtained is insoluble in water, alcohol and ether. Itis soluble in propylene glycol to at least 10%. This solution is stableto heating at a temperature of 80 C. for at least 4 weeks. The productsinters at 175 C. and melts with decomposition between 175 and 200 C.The aqueous suspension of the substance reduces Fehling solution slowlyon heating. The nitroprusside reaction for SH groups is negative tofaintly positive in the presence of sodium car- The same product (III)may also be obtained by converting compound (I) into the corre pondingderivative containing the Sb=0 radical by reduction in the mannerdescribed in my copending application Ser. No. 536,426, filed on May 19,1944, now Patent 2,430,462, November 11, 1947, and reacting an aqueoussuspension of the reduced compound at substantially neutral reactionwith the necessary amount of compound II.

Example 2. ,i mol of the hydrochloride of 3-amino-4-hydroxyphenylarsenoxide are dissolved in 48 m1. of water and enough sodium carbonateto form a clear solution having a pH of 6.0. With rapid stirring 1.1 ml.01; 2,3-dimercapto-propanol (11 millimols) are added. A whitish, glueyprecipitate is formed, which changes to a granular white powder uponadjusting the pH to 7.5 and continuing stirring for half an hour. Theprecipitate is filtered ed and washed abundantly with distilled water.

The product thus obtained has the formula (IV) S-CH:

S- H.CH1OH glycol. Such solution of the salt is distinguished by goodstability.

Example aa-a, mol ora-(znev-aiamino-ixszwtriazinyl-6') amino 4hydroxyphenylarsendichloride of the formula N s. on BIN- /(ENH on N/ \Nwas ts N/ s-cm It is insoluble in cold water, and soluble in propyleneglycol.

Example 1-9 moi of p-amlnophenyl arsendichloride of the structuralformula HaN-OAwCl:

prepared according to known methods. is suspended in times its weight ofwater and 1' mol of sodium carbonate, and 11 mi. (110 millimois) a of2,3-dimercapto-propanol are added with vigorous stirring. Stirring iscontinued for minutes. The precipitate formed, which is filtered off andwashed with water, corresponds to the formula It yields injectablesolutions in propylene glycol and is soluble in dilute hydrochloricacid.

Example 5.-- mol of 3-acetylamino-4-hydroxy-phenyl-arsenoxide of theformula AsO NH.C OCH:

is suspended in 60 times its weight of water, and to the reactionmixture 11 ml. (110 miliimols) of -2,3-dimercaptopropanol, dissolved inmethanol.

are added with vigorous stirring. Stirring of the reaction mixture iscontinued for 60 minutes. A light tan precipitate is formed, which isfiltered of! and washed with water.

a 6 The reaction product formed has the structural formula s-cm INECOGH:

The starting material used in this example is prepared by reduction ofs-acetylamino-a-hydroxyphenylarsonic acid according to classical methodswith sulfur dioxide in the presence of catalytic quantities of hydriodicacid.

Example 1- 5 mol of 2-hydroxy-4-acetylamino-benzene-arsendichloride ofthe formula AsCh NH.OOC I is suspended in 50 times its weight of water,and to the suspension E mol of sodium carbonate and 11 ml. miliimols) of2,3-dimercaptopropenol are added with rapid stirring. The resultingprecipitate is filtered off, washed with water and dried in vacuo.

The reaction product thus formed has the structural formula The compoundis insoluble in water, soluble in propylene glycol, ethylene glycol,glacial acetic acid, and hot ethanol.

Example 7.30 miliimols of i-carbamidophenylarsonic acid of the formulaAsOrILNa are suspended in 400 ml. of water. and a concentrated (50%)aqueous solution of millimols of ammonium thiogiycolate is added. Thereaction mixture is stirred in an inert atmosphere at a temperature of80 0., for 60 minutes. To the resulting solution are added dropwise withrapid stirring 33 miliimols of 2,3-dimercapto propanol. A whiteprecipitate separates from the solution, which is filtered off, washedwith water, and dried in vacuo.

The compound formed corresponds to the formula NELC ONE:

The compound is insoluble in water. chloroform and ether, soluble inpropylene glycol.

Example 8.36.4 millimols of sodium N-phenylglycine-amide-p-arsonate ofthe formula its OaH.Na

NELC H1O ONHI NPLCHsC ONH:

It is insoluble in water and soluble in propylene glycol.

Example 9.--36.4 millimols of the monosodium salt of4-hydroxypropylamoniphenyl-l-arsonic acid of the formulamnom-O-xmcmhcmon are added to a solution of 218 millimols of ammoniumthioglycolate in 500 ml. of water. The reaction mixture is heated at 80with stirring in an inert atmosphere for 45 minutes. To the resultingsolution 40 millimols of 2,3-dimercaptopropanol, dissolved in 20 ml. ofethanol, are added with vigorous stirring. A precipitate is formed,which is filtered off, washed with water and dried in vacuo.

This precipitate consists of a compound of the following formula:

HrC-S )AsONIMCHDaCEbOH If in the above example instead of the sodiumsalt of 4-hydroxypropylaminophenyl-l-arsonic acid, an equivalent amountof the monosodium salt of 4-hydroxyethylaminophenyl-l-arsonic acid isused under otherwise similar conditions,

a compound corresponding to the following formula is obtained:

The product is insoluble in water. It is soluble in propylene glycol andhot ethanol.

Example 10.--To a 5% aqueous solution containing 50 millimols of sodiump-aminophenylstibonate of the formula H2N.CsH4.SbO(OH) (ONa) a 20%aqueous solution of 300 millimols of potassium thioglycolate are addedat room temperature with rapid stirring, which is continued for about 1hour. To the resulting clear solution 55 millimols of2,3-dimercaptopropanol, dissolved in 20 ml. of ethanol are added withconstant vigorous stirring. The reaction product separates from thesolution in form of a brownish gummy precipitate which is filtered off,and washed with water. The compound formed has the formula nus-Gs l Itis insoluble in water but soluble in propylene glycol and sulfuric acid.

Example 11.--To a 2% aqueous solution containing 40 millimols of thesodium acetylaminophenylstibonate of the formula CI-l's.CO.NH.CsI-I4.SbO(OH) (ONa) a 55% aqueous solution containing 240 millimols of ammoniumthioglycolate are added at room temperature with rapid stirring. Thestirring is continued for 30 minutes. To the resulting solution 45millimols of 2,3-dimercaptopropanol are added with vigorous stirring. Aprecipitate is formed, which is filtered off and washed with water. Thecompound formed has the formula It is insoluble in water. Injectablesolutions may be prepared by dissolving the product in warm propyleneglycol.

A compound of the formula S-CH:

c1 cine owe-Gs may be obtained by a procedure substantially identicalwith that described above, if an equivalent amount of sodium3-chloro-4-acety1aminophenylstibonate is substituted for the,monosodium-p-acetylaminophenylstibonate in the above example.

Example 12.36.4 millimols of the disodium salt ofs-diphenylcarbamide-4,4'-distibonic acid, of the formula NHObOsHNo areadded to a solution of 218 millimols of sodium thioglycolate in 1 literof water with rapid stirring at room temperature. The stirring iscontinued for 30 minutes. To the solution thus formed, millimols of2,3-dimercaptopropanol are added dropwlse with rapid stirring. Aprecipitate is formed which is filtered oil and washed with water.

The reaction product formed has the formula B-CH:

The product is insoluble in water, but soluble in propylene glycol.

Example 13.To mol of p-aminophenylarsenoxide of the formula suspended in1 liter of water are added 110 millimols of 2,3-dimercaptopropanoldissolved in 50 ml. of ethanol with rapid stirring. Stirring iscontinued for 1 hour. The resulting product has the formula s-c HI Thisproduct, which is identical with that obtained in Example 4, is washedwith water and is then reacted with an aqueous suspension of mol of2,4-diamino-6-chioro-1,3,5-triazine with stirring at a temperature of100 C. at a pH of 2-4. The resulting reaction product corresponds to theformula It is insoluble in water, cold ethanol and methanol, but solublein propylene glycol.

Example 14.--1 mol of a compound corresponding to the formula issuspended in 50 times its weight of water and 11 ml. (110 millimols) of2,3-dimercaptopropanol are added to the solution with vigorous stirring.After 50 minutes of continued stirring the compound formed is filteredoil and washed with water. The reaction product, which is soluble inpropylene glycol, corresponds to the formula Bio-Om Example 16.--36.4millimols of sodium pmelaminylphenylstibonate are suspended in ml. ofwater and to this solution 218 millimols of ammonium thioglycolate areadded in a 55% aqueous solution. The reaction mixture is stirred at roomtemperature for 15 minutes to form a solution having a pH of about 9.The pH is adiusted to 6.5-7 by the addition oi aqueous acetic acid, thereaction mixture is filtered and the clear filtrate is diluted with 200ml. of water. 40 millimols of 1,2-propanedithiol are now added to thesolution with rapid stirring. A white precipitate is formed which isfiltered off, washed with water, and dried in vacuo over concentratedsulfuric acid.

In the above example. equivalent amounts or ethanedithiol (SH.CH2.CH2SH)or 2,3-butane dithiol may be substituted for the 1,2-propanedithiol. Thedithiols mentioned in this example may be prepared according to themethods described in the U. S. Patent 2,402,643, granted to W. A. Lazieret 8.1.

Example 17.-y mol of the hydrochloride of3-amino-4-hydroxyphenylarsenoxide and the requisite amount of sodiumcarbonate are dissolved in 48 ml. of water to form a clear solutionhaving a pH of 6.0. To the solution 11 millimols or 1,2-propanedithiolare added with rapid stirring, and stirring is continued for half anhour. A white precipitate is iormed which is filtered oh and washed withdistilled water.

By substituting equivalent amounts of 1,2- ethanedithiol or2,3-butanedithiol tor the 1,2-propane dithiol used in this exampie, andproceeding in a substantially identical manner, correspondingderivatives containing ethanedithiol and 2,3- butaneditnioi,respectively, are obtained.

Example 18.'J.'0 an aqueous suspension of 36.4 millimols of sodiump-melaminyipnenylstibonate in 100 ml. 01 water, a 55% aqueous solutionof 218 miiliinois or ammonium thiogiycolate is added with stirring Iorabout 10 minutes. The pa oi the soiution is ao usted to (5.0-1 by theaddition or dilute aqueous acetic acid. The reaction mixture is filteredand the clear filtrate is diluted with 200 ml. or water. To the dilutedsolution 40 millimols OI 1,3-cuthioglycerol are added with rapidstirring. A whitish precipitate is iormed which is filtered 011, washedwith water, and dried in vacuo over concentrated suliuric acid. Example19.--To a solution consisting of mm or the hydrochloride or3-amino-4-hydroxypnenyiarsenoxide and the requisite amount or 50- mmcarbonate to yield a mi 01 6 in e80 ml. of water, millimols ori,3-dithioglycerol are added with vi orous stirring. A giuey precipitateis formed which changes to a white powder upon ad- Justing the pri. to(.0 and continued stirring Ior hair an hour. The precipitate is filteredoff, washed with water and dried prei'erauly under vacuum in thepresence or concentrated sulruric acid.

Example 20.To a 5% aqueous solution con taming 56.4 millimols or sodiump-aminophenyl- 11- 1,2-propanedithiol are added with vigorous stirring.The resulting precipitate is filtered off, washed with water, and driedunder vacuum in the presence of concentrated sulfuric acid.

Analogous cempounds may be obtained by substituting equivalent amountsof 1,2-ethanedithiol or 2,3-butanedithiol for the 1,2-propanedithiolused in the above example.

Ewample 21.-100 millimols of p-aminophenyl arsendichloride are suspendedin 1 liter of water and 200 millimols of sodium carbonate and 110millimols of 1,2-propanedithiol are added with vigorous stirring whichis continued for 60 minutes. The reaction product formed is filteredoff, washed with water, and dried under vacuum.

Analogous compounds may be obtained by proceeding in substantially thesame manner as set forth in the above example, by substituting anequivalent amount of 1,2-ethanedithiol or 2,3- butanedithiol for the1,2-propanedithiol used.

Example 22.36.4 millimols of sodium pmelaminylphenylstibonate aresuspended in 100 ml. of water and .to this suspension 218 millimols ofpotassium thioglycolate are added with stirring in 20% aqueous solution.Stirring is continued for minutes and the pH of the reaction mixture isthen adjusted to 6.5-7 by the addition of dilute aqueous acetic acid.After filtration, the reaction mixture is diluted with 300 ml. of waterand to the diluted solution 40 millimols of 1,2-dimercaptobenzene,dissolved in alcohol, are added with rapid stirring. The precipitateformed is filtered ofi. and washed abundantly with water.

The washed precipitate is dried in vacuo over concentrated sulfuricacid.

Example 23..To an aqueous solution consisting of 36.4 millimols ofsodium p-melaminyh phenylstibonate and 100 ml. of water, 218 milli--mols of potassium thioglycolate are added in 20% aqueous solution andthe reaction mixture is stirred at room'temperature for 10 minutes. ThepH is adjusted to 6.5-7 by the addition of dilute aqueous acetic acid.The reaction mixture is filtered, the filtrate is diluted with 300 ml.of water and to the diluted liquid 40 millimols of dithio-o-xylyleneglycol of the formula CGHA (CHzSH) 2 dissolved in alcohol, are addedwith rapid stirring. A whitish precipitate is formed which is filteredoff, washed with water, and dried in vacuo over concentrated sulfuricacid.

Example 24.To a neutral solution prepared by dissolving 100 millimols ofthe hydrochloride of 3-amino-4-hydroxyphenylarsenoxide and the requisiteamount of sodium carbonate in 480 ml. of water, 110 millimols of1,2-dimercaptobenzene, dissolved in ethyl alcohol, are added with rapidstirring, whereupon a whitish precipitate is formed. Stirring iscontinued for about half an hour. The precipitate is filtered off,washed with distilled water, and dried, preferably in vacuo in thepresence of concentrated sulfuric acid.

Example 25.To a neutral solution prepared by dissolving 100 millimols ofthe hydrochloride of 3-amino-4-hydroxyphenyl arsencxide and therequisite amount of sodium carbonate in 480 ml. of water, 110 millimolsof dithio-o-xylylene glycol, dissolved in ethyl alcohol, are added withrapid stirring, whereupon a whitish precipitate is formed. Stirring iscontinued for about half on hour. The precipitate is filtered off,washed with distilled water and dried, preferably in vacuo in thepresence of concentrated sulfuric acid.

Example 26'.10 millimols of sodium p-melaminyl-phenylstibonate aredissolved in 10 parts by weight of propylene glycol. 22 millimols of2,3-dimercaptoproponal are added. The resulting solution is poured withstirring into 15 volumes of water. The precipitate which is formed iscentrifuged off, washed with water and alcohol and dried in vacuo. Thereaction product is identical with the one obtained by the method ofExample 1.

For practical therapeutic purposes, it is not necessary to isolate thecompound but the solution described above containing in propylene glycolas a solvent the reaction product of sodium p-melaminyl-phenylstibonateand 2,3-dimercaptopropanol in a molar ratio of 1 mol of the former tonot less than 2 mols of the latter. can be used directly for parenteraltreatment.

Example 27.-20 millimols of sodium p-acetylaminophenylstibonate areadded to a solution of milllimols of ammonium thioglycolate in 250 ml.of water. The reaction mixture is stirred for 15 minutes giving a clearsolution of pH 9. An alcoholic solution of 22 millimols ofdithiopentaerythritol, prepared according to U. S. P. 2,402,665, isadded dropwise with rapid stirring. The resulting precipitate isfiltered off, washed with water, and dried in vacuo. The product has theformula:

scm cmon cmcomr-Qsni c sou, onion It is insoluble in water but solublein propylene glycol.

Example 28.To a suspension of 36.4 millimols sodiump-melaminylphenylstibonate in 300 m1. of water are added with stirring218 millimols ammonium thioglycolate. Stirring is continued for 15minutes. The pH of the resulting solution is adjusted to 6.57 by theaddition of aqueous acetic acid. The reaction mixture is clarified byfiltration and to the filtrate are added 40 millimols of2,3-dimercaptopropionic acid. A white precipitate is formed which isfiltered ofi, washed with water, ethanol and ether. and is dried invacuo. The product has the structure:

S-GH:

S-U H.C OOH It is insoluble in water, alcohol and ether. It is solublein water upon addition of sodium carbonate to yield clear, injectablesolutions.

Example 29.- mol of a compound corresponding to the formulaNHrz-nnOaasomc 001:

prepared in the manner of my co-pending application Ser. No. 518,998,filed on June 20, 1944, now Patent 2,422,724, June 24, 1947, isdissolved in water and to the resulting solution millimols of2,3-dimercaptopropyl ethyl ether are added with vigorous stirring. Awhite precipitate forms immediately. It is filtered off, washed 13 withwater, and dried in vacuo. The product has the structure:

' centrated sulfuric acid, a product is obtained which has the followingstructure:

S-CH2 It is insoluble in ether, chloroform, and benzene. It is solublein water to form injectable solutions.

For practical purposes, it is not necessary to isolate the product, butthe solution described above containing, in an aqueous medium, thereaction product of p-aminophenylarsenoxide and an equivalent amount of2,3-dimercaptopropanol-glucoside is suitable for parenteraladministration.

Example 31 .-To a 5% aqueous solution containing 50 millimols ofsodium-p-aminophenylstibonate, a 20% aqueous solution of 300 millimolsof potassium thioglycolate are added at room temperature with rapidstirring which is continued for one hour. To the resulting solution, 55millimols of 1,3-disulfhydroylbenzene dissolved in ethanol are addedwith constant vigorous stirring. The reaction product separates from thesolution, is filtered off and washed with water.

Example 32.-0.1 mol of sodium arsanilate is dissolved in 50 parts itsweight of water. 22 millimols of 2,3-dimercaptopropanol are added, andthe reaction mixture is stirred for 40 minutes at 80 in an inertatmosphere. Stirring is continued for 1 hour at room temperature. Theprecipitate formed is centrifuged off, washed with water andrecrystallized out of boiling methanol. The resulting white crystallineproduct corresponds to the formula B-CH:

It is insoluble in cold water, soluble in hot alcohol, dilutehydrochloric acid and propyleneglycol.

As shown in the above examples, the present invention may be applied tovarious organometallic compounds and various dithiols in order to obtainnew compounds embodying the present invention.

As preferred examples of the invention, compounds obtainable fromortho-dithiols and compounds substituted in a benzene ring by arsenicradicals or antimony radicals, including melaminylphenyl compoundssubstituted in the phenyl group by arsenic or antimony radicals, may bementioned.

14 present invention is 2,3-dimercaptopropanol. However other dithiolsof aliphatic or aromatic compounds, particularly aliphatic and aromaticorthodithiols, may also be used.

Furthermore, in the above described examples, in which thioglycolatesare first reacted with the organometallic compounds, and the reactionproducts formed are further reacted with dithiols, other thio-acidderivatives, such as thiolactates, may be be substituted for thethioglycolates.

It is to be understood that in the present specification and claims theterm amino radical is used to include NH2 radicals as well as the abovedisclosed substituted amino radicals. The abbreviation i. p." is used inthis specification to denote intra-peritoneal." The terms ortho-.dimercapto radical and ortho-dimercapto compound" are used inthe'present specification and claims to denote organic radicals andcompounds in which two --SH radicals are attached to vicinal carbonatoms of said radicals and compounds respectively.

It will be apparent from the above description that my invention is notlimited to the specific compounds and process steps described above andmay be carried out with various modifications without departing from thescope of the invention as defined in the appended claims.

What I claim is:

l. A new organometallic compound correspending to the formula wherein Ris an ethylene radical substituted by a member of the group consistingof -CH:OH. and CH2OC2H5.

2. A compound having the following formula:

ERNST A. H. FRIEDHEIM.

References Cited in the file of this patent UNITED STATES PATENTS S C H:HEN-1 vol. H, "Chemotherapy, Reinhold Pub. Corp. 1946, pp. 99-100.

Sandground et al., The Journal of Pharmacology and ExperimentalTherapeutics, vol. 78, No. 2, June 1943. pp. 109-114.

'lhopdmddithioluodincaminlouttho u OMLChIl-BocJOSLprttpJMS-B'l.

1. A NEW ORGANOMETALLIC COMPOUND CORRESPONDING TO THE FORUMAL